RAGE and its ligands in cancer – culprits, biomarkers, or therapeutic targets?

Tesařová, Petra; M, Cabinakova; Mikulova,; Zima, Tomáš; Kalousová, Marta

doi:10.4149/neo_2015_061

Cited by 23 publications

(18 citation statements)

References 70 publications

(122 reference statements)

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“…This interpretation is consistent with the observation that CD166/ALCAM shares with RAGE some endogenous ligands, and is compensatorily upregulated after genetic deletion of its counterpart . In addition, it is supported by the finding that increased tumour levels of CD166/ALCAM in KCM mice treated with CML + RAP were associated with tumour spread, in keeping with the notions that this RAGE homologue is typically restricted to subsets of cells involved in dynamic growth and migration and is an independent prognostic marker for poor survival and early tumour relapse in PaC . However, the findings in mice treated with CML + RAP should be confirmed in RAGE knockout mice treated with CML, although, in our hands, RAP treatment provided similar protective effects to those induced by RAGE ablation in mice not treated with CML .…”

Section: Discussionsupporting

confidence: 87%

The advanced glycation end‐product N^ϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

Menini

Iacobini

Latouliere

et al. 2018

The Journal of Pathology

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Diabetes is an established risk factor for pancreatic cancer (PaC), together with obesity, a Western diet, and tobacco smoking. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs), which characterizes all of the above disease conditions and unhealthy habits. Surprisingly, however, the role of AGEs in PaC has not been examined yet, despite the evidence of a tumour-promoting role of receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Here, we tested the hypothesis that AGEs promote PaC through RAGE activation. To this end, we investigated the effects of the AGE N -carboxymethyllysine (CML) in human pancreatic ductal adenocarcinoma (PDA) cell lines and in a mouse model of Kras-driven PaC interbred with a bioluminescent model of proliferation. Tumour growth was monitored in vivo by bioluminescence imaging and confirmed by histology. CML promoted PDA cell growth and RAGE expression, in a concentration-dependent and time-dependent manner, and activated downstream tumourigenic signalling pathways. These effects were counteracted by RAGE antagonist peptide (RAP). Exogenous AGE administration to PaC-prone mice induced RAGE upregulation in pancreatic intraepithelial neoplasias (PanINs) and markedly accelerated progression to invasive PaC. At 11 weeks of age (6 weeks of CML treatment), PaC was observed in eight of 11 (72.7%) CML-treated versus one of 11 (9.1%) vehicle-treated [control (Ctr)] mice. RAP delayed PanIN development in Ctr mice but failed to prevent PaC promotion in CML-treated mice, probably because of competition with soluble RAGE for binding to AGEs and/or compensatory upregulation of the RAGE homologue CD166/ activated leukocyte cell adhesion molecule, which also favoured tumour spread. These findings indicate that AGEs modulate the development and progression of PaC through receptor-mediated mechanisms, and might be responsible for the additional risk conferred by diabetes and other conditions characterized by increased AGE accumulation. Finally, our data suggest that an AGE reduction strategy, instead of RAGE inhibition, might be suitable for the risk management and prevention of PaC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionsupporting

confidence: 87%

The advanced glycation end‐product N^ϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

Menini

Iacobini

Latouliere

et al. 2018

The Journal of Pathology

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“…An increasing number of studies have demonstrated the importance of RAGE in the pathogenesis of multiple human disease types, including cancer (38)(39)(40)(41). The deregulation of RAGE is considered to be an important factor in tumorigenesis, and the increase of RAGE is associated with a diverse range of malignancies (22,42). In the present study, the results demonstrated that scutellarein treatment significantly decreased the protein levels of RAGE, but not the mRNA levels, compared with the control (P<0.05).…”

Section: Discussionsupporting

confidence: 40%

Scutellarein inhibits the development of colon cancer via CDC4‑mediated RAGE ubiquitination

Wang

Zhong

et al. 2020

Int J Mol Med

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Scutellarein has been identified to serve an anti-tumor function in human colon cancer, but the underlying mechanisms remain largely unclear. The present study further investigated the effect and mechanism of scutellarein, extracted from wild chrysanthemum, in the progression of colon cancer. MTT, clone formation, flow cytometry and tumor-bearing mice assays were used to detect cell viability, clone formation, apoptosis and tumorigenesis, respectively. Western blot and quantitative PcR assays were performed for protein and mRNA expression detection. The results revealed that, compared with the control group, scutellarein treatment significantly inhibited the viability and induced the apoptosis of colon cancer cells (P<0.05), with significant decreases in receptor for advanced glycosylation end products (RAGE) protein expression and stability and an increase in RAGE ubiquitination (P<0.05). However, the effects of scutellarein exerted in cell apoptosis and viability were rescued by RAGE overexpression, and accelerated by RAGE knockdown. Additionally, it was observed that scutellarein treatment induced a significant increase in the expression of cell division control protein 4 (cdc4) compared with the control group (P<0.05), which was then verified to interact with RAGE protein and mediate its ubiquitination. Overexpression of cdc4 inhibited colon cancer cell viability and promoted the apoptosis of SW480 and T84 cells, whereas this function was weakened when RAGE was overexpressed. Furthermore, CDC4 downregulation significantly neutralized scutellarein functions in promoting cell apoptosis and inhibiting cell viability and tumorigenesis in colon cancer cells compared with the scutellarein group (P<0.05). In conclusion, the present study revealed that scutellarein inhibited the development of colon cancer through upregulating cdc4-mediated RAGE ubiquitination.

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“…The interaction between RAGE and its ligands plays an important role in critical cellular processes, such as proliferation, apoptosis, and migration (Tesarova et al, 2015). In gastric cancer, knockdown of RAGE reduced the proliferation and invasion of cells, implying that RAGE promotes the proliferation and invasion of cancer cells (Xu et al, 2013;Wang et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Receptor for advanced glycation end-products (RAGE) is overexpressed in human osteosarcoma and promotes the proliferation of osteosarcoma U-2OS cells in vitro

Zhang¹,

Jin²,

Cf³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Osteosarcoma (OS) is an aggressive cancer of the long bones, and usually affects children and young adults. The receptor for advanced glycation end-products (RAGE) has recently been recognized as an oncogenic receptor that binds to different ligands, and promotes the progression of various cancers. However, little is known about the association between RAGE and the pathogenesis of OS. In this study, we first examined the expression of RAGE in OS tissues using immunohistochemical staining, western blotting, and reverse transcription quantitative polymerase chain reaction. We then determined the influence of the overexpressed RAGE on the proliferation of U-2OS cells in vitro. The results showed that RAGE was overexpressed in OS tissues compared with peritumor tissues, at both the mRNA and protein levels, and there was a significant association between overexpressed RAGE and clinicopathological characteristics, such as clinical stage and distant metastasis. Moreover, the overexpression of RAGE in U-2OS cells significantly promoted their proliferation in vitro. In conclusion, this study indicated that RAGE is overexpressed in OS tissue and promotes the proliferation of U-2OS cells. These data imply that RAGE promotes the growth of OS, and is a potential diagnostic biomarker and therapeutic target for the disorder.

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RAGE and its ligands in cancer – culprits, biomarkers, or therapeutic targets?

Cited by 23 publications

References 70 publications

The advanced glycation end‐product N^ϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

The advanced glycation end‐product N^ϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

Scutellarein inhibits the development of colon cancer via CDC4‑mediated RAGE ubiquitination

Receptor for advanced glycation end-products (RAGE) is overexpressed in human osteosarcoma and promotes the proliferation of osteosarcoma U-2OS cells in vitro

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RAGE and its ligands in cancer – culprits, biomarkers, or therapeutic targets?

Cited by 23 publications

References 70 publications

The advanced glycation end‐product Nϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

The advanced glycation end‐product Nϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

Scutellarein inhibits the development of colon cancer via CDC4‑mediated RAGE ubiquitination

Receptor for advanced glycation end-products (RAGE) is overexpressed in human osteosarcoma and promotes the proliferation of osteosarcoma U-2OS cells in vitro

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The advanced glycation end‐product N^ϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention

The advanced glycation end‐product N^ϵ‐carboxymethyllysine promotes progression of pancreatic cancer: implications for diabetes‐associated risk and its prevention